US8206622B2 - Process for production of ionically crosslinked polysaccharide microspheres - Google Patents

Process for production of ionically crosslinked polysaccharide microspheres Download PDF

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US8206622B2
US8206622B2 US10/590,316 US59031605A US8206622B2 US 8206622 B2 US8206622 B2 US 8206622B2 US 59031605 A US59031605 A US 59031605A US 8206622 B2 US8206622 B2 US 8206622B2
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process according
polymer
gelling solution
solution
weight
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US20070178162A1 (en
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Stefan Kammermeier
Till Merkel
Katharina Schmid
Achim Müller
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Eyesense AG
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Eyesense AG
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B01J13/04—Making microcapsules or microballoons by physical processes, e.g. drying, spraying
    • B01J13/046—Making microcapsules or microballoons by physical processes, e.g. drying, spraying combined with gelification or coagulation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B01J13/06—Making microcapsules or microballoons by phase separation
    • B01J13/14—Polymerisation; cross-linking

Definitions

  • the present invention relates to a process for the production of microspheres comprising an ionically crosslinkable polymer and to a system for carrying out the process.
  • ionically crosslinkable polymer refers to a soluble polyionic polymer that is capable to instantaneously form a sparingly or insoluble gel on contact with a gelling solution comprising divalent, multivalent or polyvalent ions having charges opposite to those of the ionically crosslinkable polymer.
  • Polyionic polymers that may be employed in the present application comprise polyanionic and polycationic polymers of natural or synthetic origin.
  • the crosslinkable polymer is a natural or synthetic polycation which can be crosslinked by multi- or polyvalent anions.
  • Natural polycations are e.g. amino functionalized polysaccharides like chitosan, amino-dextran, or polypeptides like protamine.
  • Synthetic polycations are e.g. poly (allylamine hydrochloride), poly(ethylen imine), poly (diallyldimethylammonium chloride) and polyamide-polyamine-epichlorhydrine.
  • anionic polysaccharides which are copolymers of monosaccharides comprising a carboxylic acid group, herein referred to as “anionic polysaccharides”.
  • anionic polysaccharides have found widespread application in formulation techniques.
  • a particularly useful characteristic of many anionic polysaccharides is their ability to be readily soluble as free acids and/or salts of monovalent cations while forming strong gels on contact with divalent or polyvalent cations.
  • anionic polysaccharides which instantaneously form gels by reaction with divalent or polyvalent cations, are called “ionically crosslinkable anionic polysaccharides”.
  • Alginic acid is a naturally occurring unbranched binary copolymer of guluronic acid (G) and its C-5 epimer mannuronic acid (M). It has been found that the G- and M-units are joined together in a blockwise fashion.
  • the salts of alginic acids are generally named alginates. Alginates are extracted in large amounts from brown seaweed. The proportions of G and M in the polymer, and the distribution of G and M blocks in the polymer, depends on the source of the alginate (Cf. Carbohydrates in Europe 1996, 14, 6-31).
  • alginate gel formation is achieved with calcium ions.
  • alginate form gels with most di- and multivalent cations.
  • Monovalent cations and Mg 2+ ions do not induce gelation while ions like Ba 2+ and Sr 2+ will produce stronger alginate gels than Ca 2+ .
  • the gel strength is dependent upon the guluronic acid content and also on the average number of G-units in the G-blocks.
  • Crosslinked alginates are used, for example, as rheology control additives, as wound dressings or for immobilizing materials such as plant cells, mammalian cells, yeasts, bacteria, vaccines or food products. Alginate gel formation is achieved with calcium ions in most applications.
  • a number of different methods for the immobilization of biomaterials in alginate beads have been developed.
  • a commonly used way to form alginate gel beads is by adding an alginate solution dropwise to a solution of gelling ions, for example calcium chloride.
  • the droplet size will determine the size of the spheres.
  • a syringe needle has been used for the formation of alginate droplets.
  • reduction in bead size is limited by the syringe needle diameter and the viscosity of the solution.
  • beads with a diameter of less than 1 mm are difficult to produce.
  • Reduction in bead size has been attempted by air jets impinging on the needle (Miyawaki et al., Agric. Biol. Chem. 1980, 44, 2865), electrostatic pulses (EP 0 167 690 B1) or vibrating needles (Hulst et al., J. Chem. Technol. Biotechnol. 1985, 35B, 198).
  • microspheres with a mean diameter of about 10 ⁇ m there is a demand for microspheres with a mean diameter of about 10 ⁇ m, since stable non-sedimenting suspensions may be prepared comprising microspheres of this size, and because microspheres having a diameter of 10 ⁇ m or less may be taken up by cells allowing a more efficient drug release inside cells (D. T. O'Hagan, J. Anat. 189, 1996, 477-482).
  • Fine droplets of an alginate solution may be generated by using a spray head, as disclosed, for example, in U.S. Pat. No. 5,387,522 and U.S. Pat. No. 6,465,226.
  • Alginate particles having a diameter of about 200 ⁇ m to about 300 ⁇ m have been obtained by the above method.
  • Ca-alginate microspheres may also be obtained by using emulsification methods. Ponceiet, et al., Appl. Microbiol. Biotechnol 1995, 43, 644 have described the production of alginate microspheres by emulsification/internal gelation of alginate sol dispersed within vegetable oil. Gelation was initiated within the alginate sol by reduction in pH releasing calcium from an insoluble complex. Alginate microspheres with mean diameters ranging from 50 ⁇ m to 1000 ⁇ m were obtained.
  • Emulsification techniques for the generation of alginate microspheres are using oils and/or organic solvents.
  • Sensitive biomolecules proteins, enzymes
  • oils and/or organic solvents may be incompatible with oils and/or organic solvents. Removal of oils and/or organic solvents from alginate microspheres is a tedious and incomplete process.
  • microspheres made from a crosslinkable anionic polysaccharide having a size of about 3-20 ⁇ m and being devoid of traces of oils and/or organic solvents.
  • microspheres of crosslinked anionic polysaccharides having a diameter of about 3 to 20 ⁇ m which are completely free of oils and/or organic solvents may be obtained by generating fine liquid aerosol droplets from a solution of a water soluble anionic polysaccharide into a stream of a gas and subsequently introducing the stream of gas comprising these droplets into a gelling solution comprising gel-forming cations.
  • the invention relates to a system for preparing microspheres comprising an ionically crosslinked polymer, the system comprising
  • the agitation means ( 11 ) are selected from tools which are known from the formation of dispersions or emulsions.
  • Preferred agitation means is ultrasound.
  • FIG. 1 is a schematic picture of the system for the production of microspheres according to the invention.
  • FIG. 2 is a size distribution of alginate microspheres manufactured by the process of the invention.
  • FIG. 3 is a picture of alginate microspheres manufactured according to the process of the invention wherein the diameter of selected microspheres has been determined.
  • a device as being used in air conditioning systems for air moistening may be used.
  • a suitable nebulizer is, for example, the air moistening device SCA 1000, manufactured by Stulz GmbH, D-22457 Hamburg.
  • the radiator coil ( 4 ) is connected to means for keeping the temperature of the solution to be nebulized at a predetermined range.
  • Preferred temperature ranges of the solution to be nebulized are of from 15 to 50° C., in particular of from 25 to 35° C.
  • the lower part of the tubing which submerges into the gelling solution comprises dispenser holes ( 12 ).
  • the process of the invention may be carried out with different ionically crosslinkable polymers.
  • Preferred crosslinkable natural polyanions are selected from the group consisting of an alginic acid, a carrageenan, a cellulose sulphate, a dextran sulphate, a gellan, a pectin and water soluble salts thereof.
  • Most preferred anionic polysaccharide is alginic acid or a water soluble salt thereof.
  • crosslinkable natural polyanions are Na + -, K + -, NH 4 + -, and Mg 2+ -salts of alginic acid and Na + -, K + -, and NH 4 + -salts of gellan, carrageenan and cellulose sulphate.
  • the liquid to be nebulized ( 3 ) comprises the crosslinkable natural polyanion in a concentration of from 0.1% to 5.0% by weight, particularly of from 0.75% to 1.5% by weight.
  • a particularly preferred liquid to be nebulized comprises of from 0.75% to 1.5% by weight low viscosity sodium alginate.
  • Preferred crosslinkable synthetic polyanions are selected from the group consisting of linear or branched polyacrylic acid, poly (meth)acrylic acid, polystyrene sulfonate, polyanions of the group of polyphosphazenes, and copolymers and water soluble salts thereof.
  • Preferred crosslinkable natural polycations are selected from the group consisting of amino functionalized polysaccharides like chitosan, amino-dextran, polypeptides like protamine and water soluble salts thereof.
  • Preferred crosslinkable synthetic polycations are selected from the group consisting of poly allylamine, poly(ethylen imine), poly (diallyidimethylammonium chloride), polyamide-polyamine-epichlorhydrine, (amino-)dextrans, polypeptides and water soluble salts thereof.
  • the stream of gas may be generated by pressurized air.
  • gases in particular inert gases, for example nitrogen or argon, are also well suited.
  • the gas should be purified before usage.
  • the gelling solution comprises a salt of a gel-forming di- or multivalent cation or anion, polyvalent cation or anion, e.g. water soluble salts of polycations or polyanions, depending on the nature of the crosslinkable polymer.
  • the gelling solution for natural or synthetic polyanions comprises a salt of a gel-forming di-, multi- or polyvalent cation in a concentration of from 0.1% by weight up to saturated solutions.
  • Preferred concentrations of the salt comprising a gel-forming di- or multivalent cation are 0.5 to 5% by weight.
  • Gel-forming di- or multivalent cations are, for example, Pb 2+ , Be 2+ , Ca 2+ , Ba 2+ , Sr 2+ Zn 2+ , Cu 2+ , Mn 2+ , Co 2+ , Fe 2+ , Fe 3+ , Al 3+ and Sn 4+ .
  • alginate microspheres by the present process, it is preferred to apply a gel-forming cation selected from the group consisting of Ba 2+ , Sr 2+ , and Ca 2+ . Most preferred cation for crosslinking alginate is Ca 2+ .
  • Gel-forming polyvalent cations are, for example, poly(allylamine hydrochloride), poly(ethylene imine), poly(diallyidimethylammonium chloride), polyamide-polyamine-epichlorhydrine, chitosan, amino-dextran, and protamine sulfate.
  • the gelling solution for natural or synthetic polycations comprises a salt of a gel-forming multi- or polyvalent anion in a concentration of from 0.1% by weight up to saturated solutions.
  • Gel-forming multivalent anions are, for example, phosphate, sulfate, citrate, oxalate, borate.
  • Gel-forming polyvalent anions are, e.g., poly (meth)acrylic acid, polystyrene sulfonate, dextran sulfate.
  • the gelling solution has to be adapted according to the gelling characteristics of a specific crosslinkable polymer.
  • a person skilled in the art knows how to select suitable divalent or polyvalent cations or anions.
  • the gelling solution is preferably essentially aqueous, but may comprise up to 25% by weight, preferably 0 to 10% by weight of one or more cosolvents.
  • suitable cosolvents include alcohols, for example, ethanol, isopropanol, glycols, and glycerin; esters, for example, ethyl acetate; or amides, for example, dimethyl formamide.
  • the gelling solution comprises up to 1.0% by weight, in particular of from 0.05 to 0.15% by weight of a surfactant.
  • Suitable surfactants are, for example, polyoxyethylene-sorbitans (e.g., TWEEN®), polyoxyethylated glycol monoethers, or surfactants comprising a block copolymer of ethylene oxide and/or propylene oxide (e.g. poloxamers or poloxamines).
  • a particularly preferred surfactant is poly(oxyethylene)20-sorbitane monolaureate (TWEEN® 20).
  • the gelling solution may additionally comprise polyelectrolytes which stabilize the crosslinked microspheres by a surface coating.
  • the alginate microspheres prepared by the method described in the invention are the first microspheres in the low micrometer range which are produced without using an emulsion method.
  • no oil or non polar organic solvent is needed which might interfere with biomolecules or living cells. Therefore, no subsequent tedious purification steps are required to remove any residual oil or non polar organic solvent.
  • Small alginate microspheres can be added to solutions (e.g. juice, medicinal drops) without sedimentation.
  • solutions e.g. juice, medicinal drops
  • a homogenous suspension of a drug entrapped in an alginate microsphere can be prepared.
  • microspheres with a mean diameter below 10 ⁇ m can be taken up by a cell which allows a more efficient drug release inside cells.
  • a 1% wt. solution of sodium alginate (Sigma, from brown algae macrocystis pyrifera (kelp), low viscosity) in ultra pure water is filled into the nebulizing chamber ( 2 ) of a system according to FIG. 1 .
  • the temperature of the radiator coil ( 4 ) is adjusted to maintain a temperature of from 25 to 30° C. in the nebulizing chamber.
  • the transfer tubing ( 8 ) is dipped into an ultra sound bath (35 kHz) which is filled with 1500 ml of a gelling solution of 5% by weight of CaCl 2 and 0.1% by weight of TWEEN 20 (Poly(oxyethylene)20-sorbitane monolaureate) in water.
  • the pressured air is adjusted to produce a slight stream of air bubbles through the CaCl 2 bath.
  • the ultra sound generator is turned on for 30 min.
  • the precipitation bath turns turbid which indicates the formation of alginate spheres.
  • the alginate—CaCl 2 mixture is filtered though a 50 ⁇ m screen cloth.
  • the alginate microspheres are separated from the CaCl 2 bath by centrifugation (10 min, 1000 ⁇ g) and decanting of the supernatant.
  • the size of the alginate microspheres was determined to be between 5 and 10 ⁇ m by microscopy imaging (see FIG. 3 ).

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  • Health & Medical Sciences (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Processes Of Treating Macromolecular Substances (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Manufacturing Of Micro-Capsules (AREA)
US10/590,316 2004-02-23 2005-02-22 Process for production of ionically crosslinked polysaccharide microspheres Active 2027-04-25 US8206622B2 (en)

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EP04003989 2004-02-23
EP04003989 2004-02-23
EP04003989.3 2004-02-23
PCT/EP2005/001850 WO2005079970A1 (en) 2004-02-23 2005-02-22 Process for production of ionically crosslinked polysaccharide microspheres

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EP (1) EP1742729B8 (de)
CN (1) CN100431684C (de)
AT (1) ATE442195T1 (de)
CA (1) CA2557107C (de)
DE (1) DE602005016540D1 (de)
ES (1) ES2334238T3 (de)
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US10117613B2 (en) 2010-10-06 2018-11-06 Profusa, Inc. Tissue-integrating sensors
US11331018B2 (en) 2016-12-22 2022-05-17 Profusa, Inc. System and single-channel biosensor for and method of determining analyte value

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CN119869382A (zh) * 2024-12-26 2025-04-25 深圳市第二人民医院(深圳市转化医学研究院) 一种海藻酸钠凝胶微球的制备装置及制备方法

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10010272B2 (en) 2010-05-27 2018-07-03 Profusa, Inc. Tissue-integrating electronic apparatus
US10117613B2 (en) 2010-10-06 2018-11-06 Profusa, Inc. Tissue-integrating sensors
US10463287B2 (en) 2010-10-06 2019-11-05 Profusa, Inc. Tissue-integrating sensors
US11331018B2 (en) 2016-12-22 2022-05-17 Profusa, Inc. System and single-channel biosensor for and method of determining analyte value

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DE602005016540D1 (de) 2009-10-22
HK1104248A1 (zh) 2008-01-11
EP1742729A1 (de) 2007-01-17
CA2557107A1 (en) 2005-09-01
US20070178162A1 (en) 2007-08-02
CA2557107C (en) 2009-04-07
ATE442195T1 (de) 2009-09-15
CN1933903A (zh) 2007-03-21
ES2334238T3 (es) 2010-03-08
EP1742729B1 (de) 2009-09-09
WO2005079970A1 (en) 2005-09-01
EP1742729B8 (de) 2010-02-03

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